TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Paroxysmal kinesigenic dyskinesia (PKD) is a common movement disorder.
• Only one-third of PKD cases are linked to proline-rich transmembrane protein 2 (PRRT2) mutations, indicating other genetic factors are involved.

Purpose of the Study:

• To investigate the genetic basis of PKD in patients without PRRT2 mutations.
• To identify novel genes associated with the development of paroxysmal kinesigenic dyskinesia.

Main Methods:

• Whole-exome sequencing (WES) was performed on 196 PRRT2-negative PKD probands.
• Case-control analysis using Gene Ranking, Identification and Prediction Tool identified candidate genes.
• Sanger sequencing screened an additional 325 PRRT2-negative PKD probands.

Main Results:

• Transmembrane Protein 151A (TMEM151A) variants were significantly more frequent in PKD patients than controls.
• Twenty-four heterozygous TMEM151A variants were found in 4.80% of probands, including missense and nonsense mutations.
• TMEM151A-related PKD cases often presented as sporadic with a pure phenotype and later onset compared to PRRT2-related cases.

Conclusions:

• Mutations in TMEM151A are associated with paroxysmal kinesigenic dyskinesia, expanding the known genetic spectrum of the disorder.
• TMEM151A-related PKD is more prevalent in sporadic cases and characterized by a pure phenotype and later age of onset.
• Further functional studies are required to elucidate the pathogenic mechanisms of TMEM151A in PKD.